The uterus of humans and mice is home to many immune cells, including natural killer (NK) and other innate lymphoid cells (ILCs), which may play important roles in pregnancy. The uterine mucosa dynamically adapts to both the menstrual cycle and pregnancy and therefore it is particularly hard to study.

A paper in Nature Communicationsby Iva Filipovic in Dr Francesco Colucci’s group at the Department of Obstetrics and Gynaecology, implicates tissue-resident NK cells as a hub for crosstalk with both maternal and fetal cells in the mouse uterus. The study was done in collaboration with Russell Hamilton of the Centre for Trophoblast Research and two groups in Genoa and Rome. Using RNA-sequencing data, Filipovic and collaborators provide the first molecular atlas of uterine NK cells and related ILCs at mid-gestation. They also identify key stages in reproductive life when these cells may play different roles, including perhaps ‘memory’ of previous pregnancies.

Dr Francesco Colucci, the senior author of the paper said: ‘This is a useful resource for future studies in reproductive immunology. Ultimately, we want to understand how maternal immune cells regulates placentation and use this knowledge to develop approaches for predicting and treating disorders of pregnancy.’

CTR manager Professor Gordon Smith took part in a Channel 4 documentary on stillbirth screened on 18 October. The aim of the documentary was to raise awareness and to underline the importance of monitoring placental functions during pregnancy as stillbirths are often linked to placental malfunctions.

The University has funded an SRI in Reproduction that aims to bring together the biological, social and clinical sciences with the arts and humanities to provide a multidisicplinary approach to current challenging topics in reproduction, such as inheritance, artificial gametes and embryos, and parenting. The Centre for Trophoblast is part of this new exciting venture that will bring together humanities and sciences.

CTR Associate Romina Plitman publishes article on "Advances in Human Placental Biomechanics" in the " Computational and Structural Biotechnology Journal". Romina, now a Cambridge college lecturer, was previously one of our CTR funded PhD students. The article can be found here:

The 2018 CTR Annual conference gathered together more than 130 world experts on placental biology. Highlights included discussions on the link between caesarean sections and placenta accreta, a dangerous condition that can be life threatening for new mothers and might lead to emergency hysterectomies.

Applications are invited for a four year PhD studentship funded by The Royal Society to conduct research under the supervision of Dr Amanda Sferruzzi-Perri at the Department of Physiology, Development and Neuroscience.

Title: Role of placental endocrine malfunction in the programming of disease in offspring

Congratulations to CTR members Janne Rozemarijn Smit, Jyothi Jayaraman, Nadia Capatina and Hannah Yong who all won prizes at the 2018 PDN symposium! Janne Rozemarijn won 1st place and Jyothi joint 3rd in the 1 year PhD and MpHil category. Nadia won 1st place in the image competition. Hannah won the third price for the best postdoctoral presentation.

Warm congratulations to Romina Plitman, CTR funded PhD student, who has recently been approved for the PhD degree after a successful viva! Romina was the recipient of one of our CTR PhD studentships. We wish her all the best for the future.

Many congratulations to Professor Azim Surani from the Gurdon Institute who won the 2018 Canada Gairdner International Award along with Davor Solter of the Max Planck Institute of Immunobiology and Epigenetics, for their "discovery of mammalian genomic imprinting that causes parent-of-origin specific gene expression and its consequences for development and disease"!

Congratulations to Dr Sferruzzi-Perri who has been awarded a New Investigator Research Grant from the MRC for work on biomarkers of materno-fetal health and the role of placental endocrine mediators in normal and obese pregnancies.

Congratulations to Dr Simon Tunster who secured an Early Career Grant from the Society for Endocrinology! Simon is a CTR Next Generation Research Fellow and his current work is on nutrient transport function to explore whether elevated Phlda2 impairs nutrient transport and to identify mechanisms through which the placenta adapts in an attempt to sustain fetal growth

Mouse pre-implantation blastocyst immunostained for DNA in blue and microtubules in green. Some cells in both the trophectoderm and the inner cell mass are undergoing mitosis. Imaged by Nadia Capatina CTR PhD student.

Infertility, miscarriage, preeclampsia, and fetal growth restriction are devastating conditions for which at present there are no effective solutions. I study the connections between cell stress and placental development. The endoplasmic reticulum (ER) is the point of convergence of many cell stressors. My preliminary data support the hypothesis that induction of ER stress leads to precocious trophoblast cell differentiation at the blastocyst stage. This may impact adversely on the stem cell pool, compromising placental development and hence pregnancy outcome.

The International Society for Developmental Origins of Health & Disease (DOHaD) has awarded Professor Dino Giussani the 2017 Nick Hales Award. This award, in memory of the late Professor Nick Hales, is awarded every two years to a scientist who has made an outstanding scientific contribution to the DOHaD field.

CTR PhD student Oisin Huhn has won the first prize for best poster at the 18th Cambridge Immunology Forum, a one-day conference attended by Editors of Nature and Science who judged the posters. Oisin Huhn is a PhD student in Francesco Colucci and Ashley Moffett's laboratory both CTR leading investigators.

Many congratulations to Hannah Yong (Sferuzzi-Perri lab) who received a Harold Fox New Investigator Award and to Joanna Rakoczy (Watson Lab) and Nadejda Capatina (G. Burton group) who both received a Y.W Loke New Investigator Award at IFPA in Manchester this week.

"Smoking, lack of exercise, bad diet and our genes are all well-known risk factors for heart disease, cancer and diabetes. But, as researchers are beginning to understand, the environment in the womb as we first begin to grow may also determine our future"

New paper published by CTR team working with Michelle Oyen and Ashley Moffett. This project is a collaboration between biologists (Ashley’s group) and bioengineers (Michelle’s group). By using microfluidic technology the team has advanced how trophoblast invasion can be studied in the lab.

Dr Amanda Sferruzzi-Perri has been awarded the Andrée Gruslin Award from IFPA: the Andrée Gruslin Award is named in honour of Dr. Andrée Gruslin, a maternal-fetal medicine specialist and is offered every year to an outstanding female mid-career in the field of placental or placental-related biology. Amanda will receive the award at the IFPA meeting in Manchester later this year.

We are delighted to announce that Dr Amanda Sferruzzi-Perri has been awarded a substantial grant from the Academy of Medical Sciences Springboard in support of her project entitled: Materno-fetal resource allocation; altering placental endocrine function by IGF2.

This two-year grant will allow Amanda to investigate how the placenta remote controls the metabolism of the mother to ensure fetal nutrient allocation and growth.

Warmest congratulations to Anne Ferguson-Smith for her election to FRS. This is a fantastic achievement and recognition of her great contributions in the fields of genomic imprinting, epigenetics and placental biology.

Congratulations to Professor Dino Giussani and colleagues on their front cover picture in Journal of Physiology, which accompanies their latest paper. Their discovery, that the main component of Viagra can protect the fetal heart, may lead to valuable treatments in some complications of pregnancy. http://www.pdn.cam.ac.uk/news/viagra-protects-the-fetal-heart

Congratulations to former CTR member Selma Boulenouar for her paper 'Adipose Type One Innate Lymphoid Cells Regulate Macrophage Homeostasis through Targeted Cytotoxicity’ just published in Immunity. Selma discovered new innate lymphocytes (ILCs: including Natural killers) in adipose tissue with novel functions, including ‘physiological’ killing of Macrophages to prevent inflammation and metabolic diseases.

Next Generation Fellow Jens Kieckbusch has recently been awarded a grant by the Rosetrees Trust. This three-year award will allow Jens to continue investigating how pregnancy complications impinge on the developing immune system in the offspring. Jens has also been awarded an EMBO short-term fellowship which will enable him to establish a collaboration with Niklas Björkström at Karolinska Institutet to specifically address the effects of low birthweight on immune system development in humans

Placental dysfunction is implicated in many major complications of pregnancy associated with adverse maternal and infant outcome, such as preeclampsia, fetal growth restriction and stillbirth. Yet, despite years of intensive research, screening for these complications is still largely based upon clinical grounds rather than ultrasonic and/or biochemical assessment of placental function. One of the few widely employed methods for assessment of risk, low first trimester levels of PAPP-A (Pregnancy Associated Plasma Protein A), was identified through secondary analysis of data collected to identify new methods of screening for Down's syndrome rather than as a purposeful search for screening tests for abnormal placentation. Development of improved methods for population screening requires better mechanistic understanding of the pathways leading to placentally-related complications of human pregnancy. This is in addition to a need for identification of biomarkers which reflect the underlying pathology, while predicting associated disease with high sensitivity and specificity. In this paper, we outline some of the challenges and opportunities in this area. Furthermore, we illustrate how some of these can be addressed in research studies using the example of the Pregnancy Outcome Prediction (POP) study, a prospective cohort study conducted in Cambridge, UK. Placenta.

This research showed that a protein (known as DLK1) circulating in the mother’s blood during pregnancy is produced by the foetus and its levels may provide a readout of foetal wellbeing.

The team first used a mouse model with a genetic deletion in the Dlk1 gene to show that the circulating protein in maternal blood comes from the foetus. In normal pregnancy the metabolism of the mother is exquisitely sensitive to starvation, even a short fast can liberate maternal fat reserves to supplement the energy required for the growth of the foetus. In pregnant mice without circulating DLK1, this fasting response did not occur in the mother. As mouse embryos without Dlk1 were smaller than controls, the team hypothesised that maternal circulating DLK1 levels in pregnancy might predict pregnancy outcome in humans.

DLK1 levels were measured in the blood of women who were enrolled in the Pregnancy Outcome Prediction study carried out by the Department of Obstetrics and Gynecology, University of Cambridge. Women with infants who were small-for-gestational age (SGA) had lower levels of DLK1 than matched controls. Importantly, DLK1 levels were not reduced in pregnancies where the infant was born small but healthy, but rather that low DLK1 levels were associated with reduced growth of the foetus resulting from pregnancy complications. This means that DLK1 might in future be used in the clinic to differentiate pregnancies that might need intervention from those that are healthy but small.

This work was funded by a CTR studentship to Mary Cleaton, and the MRC.

Fellowships ad eundem are awarded by the RCOGin recognition of the work of individuals who are not Members or Fellows of the RCOG but who have demonstrated, through research or clinical commitment, major contributions to obstetrics, gynaecology or reproductive health, they have contributed to the advancement of the science or practice of obstetrics and gynaecology in a substantial way and are of an extremely high scientific calibre. Fellows ad eundem are entitled to use the suffix: FRCOG.

Professor Giussani was awarded the Fellowship specifically for the major contributions his work has made through research to obstetrics and gynaecology and to the wellbeing of women.

Congratulations to the 40 awardees of the prestigious Loke New Investigator Travel Grants at the recent IFPA meeting in Portland, Oregon. Awardees came from 16 different countries, a testimony to the depth of new talent in the field of placental biology. We wish them every success in their future careers.

Peter et al's paper The pluripotency factor Nanog regulates pericentromeric heterochromatin organization in mouse embryonic stem cells was recently published in Genes and Development. This research, led by the Babraham Institute with collaborators in the UK, Canada and Japan, has revealed a new understanding of how an open genome structure supports the long-term and unrestricted developmental potential in embryonic stem cells. This insight provides new avenues for improving the quality and stability of embryonic stem cells – an essential requirement to fulfil their promise in regenerative medicine.

How our DNA is stored and packaged in the nucleus can be viewed as two different states: regions of the genome that are ‘open for business’ and can be actively read, and regions that are locked away by being tightly packed and inaccessible to the factors that read DNA.

The researchers looked in detail at the mysterious tightly packed portions of the genome, called constitutive heterochromatin. Previous research has shown that heterochromatin is maintained in an unusually open and uncompacted organisation in embryonic stem cells, which is different to all other cell types. It is thought that this rare form of genome architecture may contribute to keeping stem cells in an unspecialised state, still full of the potential to become any cell type in the body. Why heterochromatin is organised in this way in embryonic stem cells has previously been unknown.

Iva Filipovic was awarded funding for the 5th flowcytometryUK meeting taking place in Leeds in July 2016. The funding covers both registration and accommodation and this funding was limited to a maximum of three applicants from UK. Dr Leonore Herzenberg, who developed the Fluorescence-activated cell sorting (FACS) technique with her husband Leonard Herzenberg, will be one of the speakers at the meeting, which is bringing flow and image cytometrists from all over Europe and beyond. Well done, Iva!

Jorge Lopez-Tello, from the Sferruzzi-Perri lab, recently won an Imanova Best Speaker Prize at the PDN Symposium in April 2016. It was a very closely-run competition with the prize awarded for best presentation. Well done Jorge!

"Given the risk of complications for both mother and child from gestational diabetes, our findings suggest that screening women earlier on in pregnancy may help improve the short and long term outcomes for these women" Dr Ulla Sovio, Cambridge University

Researchers have uncovered previously unappreciated means by which epigenetic information contained in the egg influences the development of the placenta during pregnancy. The research, which was performed in mice, indicates that a mother’s health, even before conception, may influence the health of her fetus, and opens questions on how a mother’s age may influence placental development.

Epigenetic information is not encoded within the DNA sequence but is critical for determining which genes are on or off. One of the ways this is achieved is via DNA methylation, a biological process where the DNA is chemically tagged to silence genes. DNA methylation marks are laid down in each egg during their development in the ovaries and, after fertilisation, some of these marks are passed onto the fetus and placenta.

In exploring the purpose of this maternal information in fetal development, focus so far has been on a small number of genes termed ‘imprinted genes’. However, there are nearly one thousand other genomic regions where methylation in the egg cell is passed onto the early embryo. The researchers set out to explore the importance of this type of methylation on the development of the placenta, a vital organ in pregnancy, and their findings are presented in the latest issue of the journal Developmental Cell.

“We were surprised to find that DNA methylation from the egg played a much larger role in placental development than methylation that was introduced after fertilisation, whereas in the embryo both are important,” explains Miguel Branco, a group leader from Queen Mary University of London who led the work. “Evolution, it seems, has granted mothers the tools to control the growth of their progeny during pregnancy by instructing on placental development.”

By using mice in which methylation of the egg’s DNA had been blocked, the researchers found that DNA methylation occurring during the development of the egg was essential for correct placental development. In particular, the research identified several genes regulated by methylation in the egg that are involved in cell adhesion and migration – both vital properties for cells of the developing placenta in establishing connections with maternal tissues to support embryo development.

“This was an exciting result for us,” said Myriam Hemberger, a group leader at the Babraham Institute. “The phenomenon of gene imprinting explains some of this but our results show that the importance of DNA methylation in early development extends beyond imprinting. Specifically, maternally-inherited DNA methylation marks are important for normal placentation as they specify cellular properties such as adhesiveness and invasive character, as well as determining the correct balance of cell types needed in the placenta.”

The research opens questions regarding the potential influence of maternal health on the fetus long before conception.

“We know that nutrition, environment and ageing affects the DNA methylation pattern in our cells, including in egg cells,” states Wolf Reik, Head of the Epigenetics programme at the Babraham Institute. “One of the questions prompted by this research is whether DNA methylation changes relating to age could contribute to the deterioration of egg quality, subsequently affecting the success of either the embryo or the supporting placenta.”

This work received support from the Biotechnology and Biological Sciences Research Council, Wellcome Trust, Medical Research Council, the EC Network of Excellence EpiGeneSys, the EC BLUEPRINT project, the Centre for Trophoblast Research, and Canadian Institutes of Health Research.

Main image description:

The egg’s epigenetic ‘blueprint’ is important for placenta development in pregnancy. Image adapted from ‘Egg sperm’ by Zappys Technology Solutions on Flickr, licensed under the Creative Commons Attribution 2.0 Generic (CC BY 2.0) license.

Publication reference:

CTR Members and Babraham Institute Researchers Paulina Latos and Myriam Hemberger have recently had a paper published in Genes & Development.

Elf5-centered transcription factor hub controls trophoblast stem cell self-renewal and differentiation through stoichiometry-sensitive shifts in target gene networks. Stem cell research led by the Babraham Institute has uncovered key new knowledge about how placental stem cells switch between maintaining a stem cell identity to setting off down the route to becoming specialised cell types. Intuitively, one would think that more of a good thing should be even better – specifically in the context of factors that maintain the self-renewing character of a stem cell. However, research from the Babraham Institute in association with the Centre for Trophoblast Research has found that this is certainly not the case for trophoblast stem cells from which the fundamental cell types of the placenta are derived. In looking at transcription factors – key orchestrators of the genes expressed in any given cell – the Babraham team observed that it is not simply their presence or absence that determines the stem cell state, but the finely tuned balance between them. See the Babraham Institute website for more details.

A special supplement of the American Journal of Obstetrics and Gynecology dedicated to the placenta has just been published http://www.ajog.org/issue/S0002-9378(15)X0002-0. Authors include CTR Director Graham Burton and CTR Scientific Advisory Board member John Kingdom.

We are delighted to welcome our latest CTR Graduate Students, Lorenzo Orietti and Iva Filipovic. Iva has just completed her MSc in Immunology at Imperial College London. She recently received the Richard Batchelor prize, awarded to the student with the best performance in the MSc. Immunology course. The student to whom the prize is awarded is chosen by the Board of Examiners and is based predominantly on examination and thesis/viva performance. Well done Iva!

Katie Skeffington, a PhD student with Dino Giussani, won best abstract by an in-training person at the 42nd International Meeting of The Fetal and Neonatal Physiological Society held in Vancouver, Canada, August 9 - 13, 2015.

Her work is on fetal origins of heart disease and uses the chick embryo as an animal model. Well done Katie!

Zhongchao Wang, a joint PhD student with Dino Giussani and the Department of Aerospace Physiology Fourth Military Medical University, Xi'an, China, won best oral presentation by an in-training person at the 42nd International Meeting of The Fetal and Neonatal Physiological Society held in Vancouver, Canada, August 9 - 13, 2015. His work is on indentifying therapy for preeclampsia using a rodent model. We warmly congratulate you, Zhongchao!

CTR Members and Researchers at The Babraham Institute, Paulina Latos and Myriam Hemberger (et al) have recently had a paper published in Nature Communications: Fgf and Esrrb integrate epigenetic and transcriptional networks that regulate self-renewal of trophoblast stem cells.

CTR Members and Researchers at The Babraham Institute, Paulina Latos and Myriam Hemberger (et al) have recently had a paper published in Nature Communications:Fgf and Esrrb integrate epigenetic and transcriptional networks that regulate self-renewal of trophoblast stem cells. In collaboration with the Centre for Trophoblast Research, University of Cambridge, they have begun to unpick the network of molecular interactions essential for trophoblast stem (TS) cells to maintain their self-renewal potential. TS cells are a stem cell population that provides a great research tool to study early processes in placental development as they can give rise to all the different cell types forming the placenta. The researchers' efforts focused on a master regulator of gene expression called Esrrb (oestrogen-related receptor beta). In mice, loss of Esrrb causes defects in placental development which means that a developing embryo cannot be supported. The researchers found that Esrrb is critical for TS cells to maintain their undifferentiated stem cell identity and once Esrrb gene expression was lost, TS cells differentiated into distinct cell types. Well done to both of you on this ground-breaking research!

Lecturer in Reproductive Biology and former NGF, Erica Watson, was recently awarded a Lister Research Prize.

Lecturer in Reproductive Biology and former NGF, Erica Watson, was recently awarded a Lister Research Prize. This award will allow the Watson group to continue to research the transgenerational effects of abnormal folate metabolism on fetal and placental development, which is work that began during her tenure as a Next Generation Fellow at the CTR. Using a mouse model, the Watson group aims to track epigenetic changes that are inherited from one generation to the next and to explore the physiological and molecular interaction between the maternal and fetal environments when folate metabolism occurs incorrectly. Ultimately, their goal is to tease apart the complex mechanism of disease inheritance caused by changes in the environment (e.g., poor nutrition).We warmly congratulate you, Erica!

Special congratulations are in order for Ulla Sovio and Gordon Smith (et al) who have had their first paper from the Pregnancy Outcome Prediction study (POPs) accepted by The Lancet.

Special congratulations are in order for Ulla Sovio and Gordon Smith (et al) who have had their first paper from the Pregnancy Outcome Prediction study (POPs) accepted by The Lancet. Screening for fetal growth restriction using universal third trimester ultrasonography: a prospective cohort study of 3,977 nulliparous women will be published this year.

Congratulations again, this time for CTR member Niu Youguo, whose poster, entitled as ‘Effects of Prenatal Hypoxia on Programmed Cardiac and Mitochondrial Function over Ageing’, has been selected for a Best New Investigator Poster Award at the 62nd Annual Scientific Meeting of Society for Reproductive Investigation at San Francisco, March 25-28, 2015.

Well done to you Niu!

More news...and more congratulations are in order! This time the good news relates to CTR PI Dino Giussani. His research group has very recently been awarded ‘The Thomas McDonald Award from the Society for Reproductive Investigation’ (SRI, previously known as the SGI). This award acknowledges the highest ranked abstract by an investigator-in-training within the field of fetal neuroscience. The award honours the legacy of Dr. McDonald, whose immense contributions to the field of obstetrics and gynaecology focused upon neuroendocrinology of the developing fetus, placental function, fetal brain development, and uterine contractibility. The first author of the work was Dr Beth Allison, a post doc from Dino's research group and Dino was the senior author. The award will be presented at this year’s international meeting of this society in San Francisco, California on March 25-28, 2015.We warmly congratulate you, Dino!

More congratulations are in order, this time for Graham Burton, Ashley Moffett and Barry Keverne for the publication of their Discussion Meeting in The Royal Society's Philosophical Transactions B. Human evolution: brain, birth weight and the immune system was published on 19th January 2015. This Theme Issue discusses the complexity of the human brain, which is unique amongst mammals. However, the large size of the brain at birth poses risks to mother and offspring due to constraints on pelvic architecture and uterine perfusion imposed by bipedalism, the so-called ‘obstetric dilemma’. Thus ensues an exploration of the complex network of interactions regulating brain development in the light of new concepts in placental evolution, the immune system at the maternal-fetal interface, and genomic imprinting. This issue is based on a Discussion Meeting held at the Royal Society in June 2014. Well done!

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